Compositions of reversible gellification are defined as solutions the variation in viscosity of which is linked to a modification of the environmental conditions. When this modification of viscosity intervenes during a change in temperature, mention will be made of thermoreversible gels and the polymers constituting the formulation are identified as “thermogelling polymers” or even “thermosensitive polymers”. These polymers are made up of hydrophobic, thermosensitive parts and hydrophilic parts. The formation of gel is explained by the auto-association of the thermosensitive portions in hydrophobic micro-domains; the entirety of the polymer being maintained in solution by the hydrophilic segments. The properties of viscosification and those of the gel are thus controlled by the respective length of the various segments and by the hydrophobic/hydrophilic ratio (L. E. Bromberg, Adv. Drug Delivery Reviews 31, (1998), 197-221).
Thermosensitive polymers are known which are intended to form thermoreversible gels in aqueous solution, the viscosity of said gels evolving reversibly as a function of their temperature. These thermosensitive polymers have hydrophobic portions which can aggregate together to form micelles when the temperature of the medium is high in order to attain that of their critical solution temperature; the hydrophilic portions linking said micelles between them. By virtue of this, an increase in the temperature of the aqueous medium in which these thermosensitive polymers are dissolved can convert it from a liquid state to a viscous state forming a gel.
Such polymers are well-known under the generic name of poloxamers. These are copolymers of blocks of propylene oxide and ethylene oxide, or polyoxyalkylenes, which can be synthesised notably according to the methods described in US patents U.S. Pat. No. 4,188,373 and U.S. Pat. No. 4,478,822. The thermosensitive polymers thus obtained enable formulating aqueous compositions which have critical solution temperatures of between 24 and 40° C. However, such formulations necessarily contain 15 to 50% of thermosensitive polymers in order to obtain a significant variation in the viscosity such that they are initially extremely viscous.
Furthermore, despite the high percentage of thermosensitive polymers that they contain, these formulations have only variations in viscosity which are less than a decade at their critical solution temperature.
More recently, pieces of work have been carried out in order to obtain compositions combining properties of thermogelling and bioadhesivity. In this light, several patents have claimed formulations of reversible gellification which are made by simple physical mixtures of a thermogelling polymer (a poloxamer) and a pH-sensitive polymer, selected from poly(carboxylic acids) (Carbopol) (U.S. Pat. No. 5,252,318, FR 2,802,097 and EP 0 551 626). At the critical solution temperature, (LCST—Lower Critical Solution Temperature), the variation in viscosity observed is about 5 to 8 times the initial viscosity, but the minimum concentration required remains high: at least 12% by mass of polymers. Poly(acrylic acids) have been mainly used for their property of adhesivity. In these latter innovations, segments of poly(acrylic acids) were chemically associated with segments of poloxamers. In addition to the bioadhesive and “pH sensitive” character, the poly(acrylic acid) part confers to the material a greater solubility in water. The presence of the hydrophilic segment promotes the solubilisation of the copolymer and thus limits the phase separation. It appears that the alternating copolymers of thermo- and pH-sensitive monomers rapidly loose their thermogelling property when the pH-sensitive monomer content increases; block copolymers are preferred.
The International Application WO 95 24430 describes graft copolymers or block copolymers of poly(acrylic acid)s (PAA) and thermosensitive polymers. The thermosensitive component of the material is ensured by Pluronics® polymers or poly(isopropylacrylamide) (NIPAm). According to the level of ionisation of the carboxylic functions, the stability of the gels and the value of the critical gellification temperature are slightly different.
The copolymerisation is carried out either by a reaction of condensation of the acid functions of the PAA with the modified reactive terminus of the Pluronic (monoamination of the hydroxy-termini)—the Pluronic-g-poly(acrylic acid) copolymer has thermosensitive grafts—, or by reaction of condensation between the poly(acrylic acid) and the poly(isopropylacrylamide), both of which are modified at a terminus by inter-condensable functions (amine and acid)—the Pluronic-b-poly(NIPAm) copolymer is formed by two blocks linked chemically.
In comparison to the physical mixtures of poloxamers and polyacids, the thermoreversible gellification of Hoffman copolymers (WO 95 24430) is obtained with compositions of lower concentrations of polymer: the formulations which contain 1 to 3% by mass of copolymer have a well-defined critical gellification temperature range of between 20° C. and 40° C., for a pH range of 4 to 8.
However, the variation in viscosity for these compositions does not attain a decade, and a phase separation into micro-domains is observed at the critical gellification temperature, and this manifests itself as an opacification of the medium. Moreover, the syntheses are carried out in several steps: a controlled modification of the terminal functions of the polymers used, condensation or chain copolymerisation, and finally separation/purification of the products desired.
After these pieces of work, Bromberg et al. described comb copolymers of poly(acrylic acid) and poloxamer, and their novel route to obtaining them (WO 97 00275). In a first step, radicals are created on the poloxamer chain by abstraction of hydrogen on the segment of poly(propylene oxide). The radical chain polymerisation of the acrylic acid is then initiated from poloxamer monoradicals.
The system obtained, which is called Smart Hydrogel™, has a perfect clarity before and at the gellification point; the sol-gel transition of aqueous solutions of low concentrations of copolymers (1 to 5% by mass) is produced in a narrow temperature interval (10° C.), between 25 and 40° C. and manifests itself by an increase in viscosity of about at least 30 times the initial viscosity. The gel thus formed behaves as a viscoelastic solid and keeps its viscosity whatever the shearing speed applied.
Two drawbacks in relation to this system were revealed by the inventors of the present invention: the bioadhesivity of the hydrogel is limited by a poor accessibility of the poly(acrylic acid) parts and the compositions have a reduced stability due to the initial oxidation of the Pluronic® polymer to create the initiating radical.
In order to improve these properties, Bromberg et al. have provided novel linear block copolymers in keeping the poloxamer and the poly(acrylic acid), as thermosensitive compound and hydrophilic compound, respectively. The originality of these copolymers is that they are composed of a central poloxamer block which is modified at its two termini by polyacid blocks. To obtain them, the two termini of the poloxamer are functionalised beforehand by acrylic or thiol groups which enable the initiation of the radical polymerisation of the acrylic acid. These triblocks show a reversible gellification at body temperature (25-40° C.), at values of pH of between 3 and 13. The solutions which are of low concentration (1 to 4% by mass) thus undergo an increase in viscosity which can go up to 2 decades.
Here again, however, the synthetic route selected is a multi-step one and it is necessary to remove the residual monomers, during or at the end of manufacture, by major treatments (extraction by Soxhlet, dialysis, multiple precipitations . . . ).
Thus, several reversible gellification systems are known to this day. Nevertheless, they necessitate a high content of solid and/or lead to a low gain in viscosity of the formulations at the LCST. Finally, the most recent systems are obtained from poloxamers having modified termini, and this necessitates multi-step syntheses and separation/purification operations which are not very compatible with an industrial production method.